Due to the ease of administration, patient compliance, and variability in formulations, the oral route of administration remains the most preferred route of administration. Amongst oral, a site specific drug delivery system remains the system of choice in many circumstances. This system can also help in optimizing oral-controlled delivery of drugs having an “absorption window” by continuously releasing the drug prior to the absorption window, for a prolonged period of time thus causing optimal bioavailability. Gastric emptying of dosage forms is an extremely variable process and the ability to prolong and control the emptying time is a valuable asset for dosage forms, which reside in the stomach for a longer period of time than conventional dosage forms. Prolonged gastric residence time and controlled-release of drugs within the gastrointestinal tract helps to reduce the dosing frequency and total dose, improve patient compliance and convenience, and maintain a less fluctuating plasma level, as well as reduce GI side effects. Prolonging of the gastric residence time of the therapeutic agents is thought to be beneficial, especially under several circumstances such as for drugs acting topically on the gastric region, for drugs with a narrow therapeutic window, for drugs with the major absorption site in the upper GI tract and for drugs that are less soluble in or are degraded by the alkaline pH of the upper GI tract.
The prior art discloses different approaches or systems to prolong the gastric residence time, such as mucoadhesive or bioadhesive systems, high density systems, expandable or swelling systems, and floating drug delivery systems.
The mucoadhesive systems are intended to extend the gastric residence time by adhering the drug to the gastric mucous membrane. Bioadhesion on soft tissues of certain natural or synthetic polymers has been exploited to control as well as to prolong the gastric retention of the delivery system. Jackson et al., in “Comparative Scintigraphic Assessment of the Intragastric Distribution and Residence of Cholestyramine, Carbopol 934P and sucralfate”, Int. J. Pharm., 212(1):55-62(2001); U.S. Pat. No. 6,207,197; and U.S. Patent Application No. 2005/0064027 describe the mucoadhesive gastroretentive system.
High density systems are intended to lodge in the rugae or folds of the stomach withstanding the peristaltic movements. Systems with a density of 1.3 g/ml or higher are expected to be retained in the lower part of the stomach. Hampson et al., “Alginate Rafts and Their Characterization”, Int. J. Pharm., 294(1-2):137-147 (2005) describe the high density gastroretentive systems.
Expandable or swelling systems are easily swallowed and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their time in the gastrointestinal tract. After drug-release, their dimensions are minimized with subsequent evacuation from the stomach. Chavanpatil et al., “Development of Sustained Release Gastroretentive Drug Delivery System for Ofloxacin: In vitro and in vivo Evaluation”, Int. J. Pharm., 304(1-2):178-184 (2005) describe the swelling gastroretentive system.
Floating drug delivery systems have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. After release of the drug, the residual system is emptied from the stomach. Arora et al., “Floating Drug Delivery Systems: A review”, AAPS PharmSciTech 6(3):E372-E390 (2005) describes the floating gatroretentive system. The floating drug system can further be classified into effervescent systems such as gas generating systems and non-effervervescent systems such as colloidal gel barrier systems, microporous compartment system, floating microspheres and alginate floating beads.
GLUMETZA® GR (metformin hydrochloride), CYTOTEC® (misoprostol), CONVIRON® (vitamin B12—combination), CIFRAN® OD (ciprofloxacin), MADOPAR® (levodopa and benserazide), and VALRELEASE® (diazepam) are some of the marketed preparations based on gastroretentive dosage forms.
U.S. Pat. No. 3,976,764 discloses solid therapeutic preparations floatable in the gastric juice wherein the active ingredient is impregnated into a body of empty globular shell or a small granular lump of a material having high buoyancy. The empty shells of the invention are gelatin capsules coated with active ingredients. The invention also discloses pop-corn or pop-rice type of materials coated with active ingredients.
Aerogels and foam materials have been used to produce floating systems. Due to entrapped air and gases in their hollow spaces, they are inherently less dense and hence float on the gastric fluids. U.S. Pat. No. 5,626,876 discloses floatable oral therapeutic systems which use microporous materials having a high void proportion for obtaining low specific gravity. The materials used are thermoplastic polymers, natural polymers and inorganic compounds such as glasses and ceramic materials. The invention relates to the preparation of microporous materials by processes such as granulation, hot melting, compression or molding. However, use of microporous materials tends to increase the bulk of the systems. There is also less flexibility for designing the dosage form and incorporating active ingredients. Such systems may also be complex and less reproducible.
U.S. Pat. No. 7,485,322 discloses a floating capsule dosage form having prolonged gastric residence time, wherein the capsule body and cap are assembled such as to encapsulate at least a tablet and granulate together with entrapped gas and is coated with a coating which is substantially insoluble or poorly soluble in an acidic medium. In this reference, the tablet and granulate comprise active and hydrophilic or lipophilic substances which helps in controlling the release. The active-release is controlled by a dual mechanism, one with the help of hydrophilic or lipophilic substances in the matrix of tablet and granulates, and second with the help of an outer coating layer. This increases the processing steps and also the complexity of the dosage form, as it would be critical to control the amount of hydrophilic and lipophilic substances in the granulate and/or tablet and to control the thickness of the coating. Further, a large amount of excipients would be required resulting in high cost. The main disadvantage with this system in particular, and with other known gastroretentive dosage systems, is that these systems release the drug after some time and there always remains the initial lag time. This may not be acceptable in instances where immediate drug-release would be required.
There is a need in the art to formulate a gastroretentive dosage system which is simple, safe, cost-effective, easy to manufacture and is functionally reproducible.
We have now developed a gastroretentive dosage system which controls the release of the active ingredient only with the help of coating, making it simple and cost-effective. Further, the gastroretentive dosage system is designed to start releasing the active ingredient without any lag time. The gastroretentive dosage system can incorporate high amount of active ingredient and therefore this system can be explored for high dose active ingredients. Further, the system can be used for pulsatile drug delivery and combination of active ingredients in particular, incompatible active ingredients.